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Zorluk: ZorGenetic and Molecular Mechanisms

A 3-week-old male infant is evaluated in the pediatric genetics clinic for profound central hypotonia, a poor suck reflex requiring nasogastric tube feeding, and cryptorchidism. The clinical team strongly suspects Prader-Willi syndrome. Arrange the following diagnostic modalities in the correct sequential order recommended to first confirm the clinical diagnosis and subsequently determine the exact underlying molecular etiology, proceeding from the initial confirmatory test to the evaluation for the rarest genetic mechanism.

  1. 1DNA methylation analysis of the 15q11.2-q13 region
  2. 2Chromosomal microarray analysis (CMA)
  3. 3Short tandem repeat (STR) polymorphism analysis of the infant and both parents
  4. 4Sanger sequencing of the SNRPN imprinting center

Cevap

The correct diagnostic sequence begins with DNA methylation analysis to confirm the diagnosis, followed by chromosomal microarray to evaluate for a microdeletion, short tandem repeat analysis to evaluate for uniparental disomy, and finally sequencing of the imprinting center to identify rare defects.
The diagnostic algorithm for Prader-Willi syndrome is strictly tiered based on test sensitivity and the epidemiological frequency of the underlying molecular mechanisms. DNA methylation is the most sensitive initial test (>99%). Once confirmed, determining the exact molecular mechanism is required for genetic counseling. The mechanisms are evaluated in order of prevalence: CMA for paternal deletion (~70%), STR analysis for maternal UPD (~25%), and finally sequencing for imprinting center defects (~1-3%).

Adım Adım Çözüm

1
Perform DNA methylation analysis.
Confirms the diagnosis of Prader-Willi syndrome.
It detects the lack of a functional paternal allele in over 99% of cases, making it the most sensitive initial screening test, though it does not identify the specific underlying mechanism.
2
Perform chromosomal microarray analysis (CMA).
Evaluates for a 15q11-q13 microdeletion.
Paternal microdeletion is the most common cause (70%). CMA is the most efficient next step to visualize this deletion once the disease is confirmed.
3
Perform short tandem repeat (STR) polymorphism analysis.
Evaluates for maternal uniparental disomy (UPD).
If CMA is negative, UPD is the next most likely cause (25%). STR compares the infant's alleles to both parents to confirm if both copies of chromosome 15 are maternal in origin.
4
Perform Sanger sequencing of the imprinting center.
Identifies imprinting center defects.
If STR shows normal biparental inheritance, an imprinting center defect (1-3%) is the only remaining cause. This step is critical because these defects can carry up to a 50% recurrence risk for future pregnancies.

Anahtar Kavram

Stepwise molecular diagnostic algorithm for Prader-Willi syndrome
Tahmini Süre:1m 30s
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Genetic and Molecular Mechanisms

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